Glomerular diseases

• 1. Normal anatomy

• 2. Pathogenesis 21 Hypersensitivity reactions

22 Pathogenetic mechanisms of glomerular diseases 23 Mechanisms of vascular injury

1 Normal anatomy

Fig. 1 Anatomy of the glomerulus and the juxtaglomerular apparatus

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Fig. 2 A podocyte surrounding a glomerular capillary All three layers (endothelium, glomerular basement membrane, slit pores between podocytes) are negatively charged Mesangium is contractable F

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GBM

Fig. 3 Glomerular basement membrane (GBM)

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2 Pathogenesis

21 Hypersensitivity reactions:

Mast cells covered with IgE antibodies bind parasite antigens inflammatory response, attraction of eosinophils killing worms

Type I: Immediate hypersensitivity (anaphylaxis)

1st exposure to antigen production of specific AB their binding to mast cells (sensitization). Next exposure allergen degranulates mast cells release of histamine (immediate response) vascular permeability, airways, hives, conjunctivitis, rhinitis. Later: leukotriens, prostaglandins, PAF, proteases (late phase) localized anaphylaxis = atopy (asthma, hay fever, eczema, hives) systemic anaphylaxis – circulatory shock, dyspnea, laryngospasm Ts activity

Type II: Antibody-dependent cellular cytotoxicity (ADCC)

Cell-mediated cytotoxicity that requires prior binding of antibodies to target cellsK(iller) cells: Lymphocyte-like cells (not B or T) that kill a variety of tumor cells and virus-infected cells but only after previous immunizationErrant or uncontrolled plasma cells produce antibodies against selfantigensDrugs combine with body antigens (e.g., on erythrocytes)

anchor and activate K-cells ADCC

AB attach to the surface of cells, bind (via Fc receptors) and activate GBM etc. neutrophils and macrophages

activate complement cascade

damage of the cells, GBM etc.

Type III: Immune-complex-mediated-hypersensitivity

Fig. 4 Immunologic reactions after injection of heterologous protein

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DEFECT IN SYSTEMS REMOVING IMMUNE COMPLEXES (PHAGOCY-TES & COMPLEMENT)

ANTIGEN EXCESS SMALLCOMPLEXES (PERSISTENT INFECTION, AUTOIMMUNITY, REPEATEDCONTACT WITH ENVIRON- MENTAL ANTIGEN)

CLEARANCE OF COMPLEXES

THEIR DEPOSITION IN TISSUES

ACUTE INFLAMMATORY RESPONSE

Deposition of complexes may reflect hemodynamic factors (glomeruli)

Type IV: Cell-mediated immune injury = delayed-type hypersensitivity

Resistant (intracellular) bacterium, foreign tissue etc. activation of TH cells TC, “angry” macrophages, K cells, N(atural) K(iller) cells (=do not require prior immunization) indiscriminate phagocytosis, exudation granulomatous inflammation, contact dermatitis, transplant rejection

22 Pathogenetic mechanisms of glomerular diseases

Three typical syndromes: nephritic, nephrotic and chronic glomerulonephritis

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Fig. 5 Etiology of glomerular injury - survey

Histology

May not correlate with theclinical presentation

Fig. 6, 7 Various histologicaltypes of glomerulonephritis

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B: “Minimal changes” GN = lipoid nephrosis: some mesangial proliferation, edematous podocytes, fusion (“loss”) of their foot processes

C: Intracapillary mesangial proliferative GN: proliferation of endothelia and mesangium, peeling off of enthelial cells from the GBM, duplication of GBM, “humps” formed by immunocomplexes

D: Crescentic GN: proliferation of all components (aggressive white cells, endo- and epithelia, mesangium, epitheloid and giant cells), leakage of fibrin. Hypersensitivity reaction type II or IV

E: Membranous GN: Precipitation of immunoglobulins on the outer surface of the GBM (“spikes” complete incorporation of Ig into the membrane)

F: Proliferative sclerotizing GN: advanced mesangial proliferation narrowing and destruction of capillaries

221 Visceral epithelial cell (= podocyte) injury

Minimal change disease = lipoid nephrosis (Fig. 7 B)

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Focal segmental glomerulosclerosis (FGS) Focal = 50% of glomeruli are affected by light microscopy Diffuse = 50% affected Segmental = only a part of the glomerular tuft is involved Glomerulosclerosis = obliteration of capillary lumens Nephrotic syndrome. Edematous podocytes, fusion (“loss”) of their foot processes. Unclear podocyte damaging toxin – some lymphokine? React on glucocorticoids

222 Immune complex formation = immune complex disease

Glomerulus is highly susceptible to the entrapment or formation of immune complexesDetection: electron microscopy, immunofluorescence (granular appearance)Location of the complexes type of injury and clinical manifestations Fig. 8 Porosity versus permeability

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2221 Subepithelial deposits

Fig. 9 left side

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Circulating complexes cannost pass through GBM in situ immune complex formation: - circulating cationic antigen, afterwards enter the corresponding antibodies - filtered autoantibody; antigen present in situ (glycoprotein on podocyte cell membrane).

CATIONIC ANTIGEN AUTOANTIBODIES

„ HUMPS“(FIG. 6C)

POSTINFECTIOUS GN (MOSTLY A, -HEMOLY-

TIC STREPTOCOCCI)

AMORPHOUS DEPO-SITS MEMBRANOUS

NEPHROPATHY. „SPIKES“(FIG. 6E)

SYSTEMIC DISEASESLUPUS NEPHRITIS

HEPATITIS B

IDIOPATHIC

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Injury to the podocytes: membrane attack complex C5b-9 fusion of the foot processes

Clinical manifestations of exclusively subepithelial deposits: typically nephrotic.

Distortion of slit diaphragms proteinuria Activated complement is not in contact with circulating inflammatory cells lack of inflammatory cell infiltration proteinuria lasts for a long time

Nephrotic syndrome

Fig. 10 Pathogenesis of symptoms

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2222 Subendothelial and mesangial deposits

Fig. 9 right side

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Typically caused by passive entrapment of preformed circulating immune complexes.The nature of the antigen whether subepithelial or subendothelial depositionLupus nephritisPostinfectious GN: Streptococci, bacterial endocarditis, hepatitis B, malariaBergerSchönlein-HenochInflammatory response - Complexes in contact with circulation generate C3a and C5a - Activation of Hageman factor coagulation cascade - Damaged endothelium cytokines and autocoids (local hormones) adhesion molecules activation of endothelial and inflammatory cells

Clinical manifestations: inflammatory and proliferative response typically nephritic syndrome:

- active urine sediment: red cells, white cells, cellular and granular casts

- GFRRecovery more rapid, but severe inflammation irreversible cell injury glomerulosclerosisHypersensitivity reaction type III

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Nephritic diseases

(Survey, Fig. 11):

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Fig. 12 Mechanisms causing reduction of GFR in the nephritic syndrome

223 Antibodies directed against GBM antigens

Antigen: noncollagenous portion of the 3 chain of type IV collagen

Complement and mediators focal glomerular necrosis, crescent formation end-stage renal failure

Anti-GBM antibodies bind in a linear pattern to the GBM (without electronoptically dense deposits)

Hypersensitivity reaction type II

Goodpasture syndrome

224 Crescent formation and cell-mediated immunity

Fig. 6D

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Severe damage of capillary wall leaks (rents) in GBM fibrinogen and other plasma components enter Bowman´s spaceCrescents = accumulation and proliferation of extracapillary cells compression of the glomerular tuft rapid renal failureCrescentic glomerulonephritis (50% glom.) rapidly progressive GNEtiology:

- any severe GN- anti-GBM antibody disease- ANCA-positive disorders

Hypersensitivity reaction type II or IV (?)

225 Alport syndromeCongenital defect of collagen

23 Mechanisms of vascular injury

231 Systemic vasculitis and antineutrophil cytoplasmatic antibodies

Acute systemic process of arteries. - Large vessel arteritides, e.g. polyarteritis nodosa distal glomerular ischemia (no inflammation) GFR - Glomerular tuft, e.g. polyarteritis nodosa, Wegener´s granulomatosis focal glomerular necrosis, crescents, active urine sedimentNovel circulating autoantibody – antineutrophil cytoplasmic antibody = ANCAHighly specific for systemic necrotizing vasculitidesANCA respiratory burst of phagocytic cells release of free radicals degranulation injury to endothelial cells

232 Thrombotic microangiopathies

Injured endothelial cell loses its natural thromboresistance platelet activation thrombi in the lumen possibly fibrinoid necrosis and fibrin deposition into mediaHemolytic-uremic syndrome: thrombocytopenia, microangiopathic hemolytic anemia, renal functionPathogenesis: - verotoxin-producing Escherichia coli damage to endothelia (infantile diarrhea); also immunosuppresives and chemotheraputics - Willebrand factor platelet aggregation; autoantibody against inhibitors of platelet aggregation - antibody-mediated endothelial injury in hyperacute renal transplant rejection

Hematuria, azotemia, hypervolemia. Mild to moderate proteinuriaPrimary and secondary (=systemic with renal involvement) diseasesThe majority is of immunologic etiology – hypersensitivity reactions type II or III Local glomerular inflammation breaking filtration membrane porosity, hematuria, proteinuria

blocking of glomerular capillaries permeability hypervolemia, uremia

Membranous GN (type E) proteinuria, rather slow Proliferating GN (type C and D) hypertension, more acute